The long-term goal of this P01 is to promote research to better understand the biology of melanomas and to translate this research to better therapies with the ultimate goal of achieving cures. Our overarching hypothesis is that intrinsic resistance to signaling inhibitors can be overcome if we take into account the genetic signatures of melanoma cells and the biological properties that are driven by intrinsic and extrinsic signals. For this competitive renewal, we will shift our focus away from the traditional targeting of kinase active sites that control canonical growth factor signaling. To achieve our goals we have developed three overarching aims, which require close coordination of projects and cores: In Aim 1 we will define cell fates for therapy of melanoma. While cell death due to apoptosis or necrosis is widely regarded to be the ultimate goal of any cancer therapy, in melanoma we now take into account two additional cell states that emerging data indicate are critical: autophagy (Projects 2 and 3) and senescence (Project 1). Our goal is to block cells from entering dormant survival states such as quiescence or pseudo-senescence and force them to die as a result of apoptosis or necrosis. In Aim 2, we will investigate the mechanism of action of signaling inhibitors. Project 4 will generate a series of novel targeted inhibitors to prevent dimer formatio of BRAF or CRAF and investigate a novel STAT3 inhibitor that resulted from recent screens. Under this aim we will combine the expertise of chemists, structural biologists and cell biologists to develop a new generation of compounds that promise a major impact on melanoma therapy in the future. In Aim 3, we will develop combination strategies for melanoma therapy. Since melanomas evolve through genetic alterations of multiple driver genes and are highly responsive to signals from the tumor microenvironment, the field has learned that single agents cannot cure by killing all malignant cells. In each project we will explore synergy among signaling inhibitor therapies using unique models for selection. The Cores for this P01 are essential for our progress in the coming funding cycle. To account for the increased needs for compound synthesis and modification, we have added a Medicinal Chemistry Core (D) in this renewal application.